Insulin-degrading enzyme (IDE) (EC 3.4.24.56, formerly listed as EC 3.4.22.11) is a zinc metallopeptidase from the M16 family that has been extensively studied due to its role in regulating cellular insulin. More recently, IDE has received considerable attention for its role in degrading amyloid β peptides, and a genetic link between IDE and late onset Alzheimer's disease has been reported. IDE degrades a number of other physiological peptides in vitro, including IGF-1 and IGF-2, glucagon, atrial natriuretic peptide, TGF-α, and γ-endorphin. In addition to its metabolic role in peptide degradation, IDE has been reported to play a role in the inhibition of proteasome function by insulin, to degrade oxidized proteins in peroxisomes, to serve as a receptor accessory factor that enhances androgen and glucocorticoid receptor binding to DNA, and to serve as a receptor for the Varicella-Zoster virus. Thus, IDE has a central role in mammalian physiology, and modulating its function can prove valuable for the treatment of disease states, most notably diabetes and Alzheimer's disease. There is a need in the art for improved understanding of the interaction between IDE and its allosteric regulators to facilitate development of compositions and methods for modulating the IDE activity.